The purpose of this 3 year, multi-site, non-randomized, prospective, observational study is to characterize the natural history of Alpers syndrome. This syndrome is a rare autosomal recessive disease caused by mutations in the polymerase gamma 1 gene (POLG), which is responsible for all mitochondrial DNA (mtDNA) replication. POLG mutations result in reduced levels of in mitochondrial DNA (mtDNA depletion), which, in turn, causes loss of mitochondrial functioning and gives rise to this disorder. Disease is characterized by seizures, liver degeneration, and progressive developmental regression (Harding, 1990). Typically, children develop normally over the first few months or years with the average age at onset of 2 - 4 years, but onset can be as late as the third decade. Alpers syndrome is thought to be a uniformly fatal disorder, but the rate of neurological degeneration, degree of liver involvement and age of death vary considerably. This disorder has been identified in diverse ethnic groups (Saneto et al., 2010). The study proposes to achieve the following specific aims: Specific Aim 1: To characterize the natural history of Alpers Syndrome stratified by POLG genotype, age of onset, sequence and timing of major symptom onset, severity and progression of organ involvement and symptom progression. If possible, to identify different phenotypes of Alpers Syndrome. Specific Aim 2: To examine possible associations between specific events in patient medical history and onset of Alpers, including viral illness, dehydration, fever, catabolic stress, including vaccination-related fever. In particular, we aim to answer the following questions: Specific Aim 3: To identify correlations between signs and symptoms of presentation of Alpers and disease severity and survival. This study is an extension of the NAMDC Clinical Registry. Patients with Alpers syndrome and their siblings will be followed for up to 2 years. Study data will include: results of tests performed as standard of care;detailed symptom information collected through diaries;neuro-developmental test results;medical history;and supplemental clinical information. At study conclusion, study data will be summarized and relevant subgroups of Alpers syndrome patients and/or their siblings will be compared using standard statistical methods in order to identify associations between genotype and phenotype and between medical history and disease course.